title: Novel solubility-switchable MRI agent allows the noninvasive detection of matrix metalloproteinase-2 activity in vivo in a mouse model.
abstract: A novel MRI proteinase-modulated contrast agent (PCA) was developed to detect the activity of the proinvasive enzyme matrix metalloproteinase-2 (MMP-2) in vivo. The PCA2-switch agent incorporates a solubility switch, where cleavage of a peptide substrate by MMP-2 decreases the water solubility of the agent. Evidence suggests that this leads to an accumulation of cleaved PCA2-switch in an MMP-2-positive, wild-type, MC7-L1 mammary carcinoma tumor in a Balb/c mouse model compared to a MC7-L1 MMP-2-knockdown tumor. When a scrambled peptide sequence is inserted into the agent (PCA2-scrambled), the in vitro cleavage efficiency of MMP-2 is markedly reduced. In vivo, PCA2-scrambled does not accumulate in the wild-type tumor and the pharmacokinetics is similar in both tumors. In conclusion, in vivo cleavage of PCA2-switch by MMP-2 results in a significant accumulation of the cleaved PCA2-switch in an MMP-2-positive tumor.
authors.affiliation: Département de Médecine Nucléaire et de Radiobiologie, Centre d'Imagerie Moléculaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Réjean
authors.initials: R
authors.lastname: Lebel
authors.forename: Beata
authors.initials: B
authors.lastname: Jastrzebska
authors.forename: Hélène
authors.initials: H
authors.lastname: Therriault
authors.forename: Marie-Michèle
authors.initials: MM
authors.lastname: Cournoyer
authors.forename: J Oliver
authors.initials: JO
authors.lastname: McIntyre
authors.forename: Emanuel
authors.initials: E
authors.lastname: Escher
authors.forename: Witold
authors.initials: W
authors.lastname: Neugebauer
authors.forename: Benoit
authors.initials: B
authors.lastname: Paquette
authors.forename: Martin
authors.initials: M
authors.lastname: Lepage
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000493:pharmacokinetics; D004789:Enzyme Activation; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010447:Peptide Hydrolases / Q000493:pharmacokinetics*
chemical_list: D003287:Contrast Media; D010447:Peptide Hydrolases; D020778:Matrix Metalloproteinase 2